Cytokine

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Not to be confused with Cytokinin. Cytokine_sentence_0

Cytokines are a broad and loose category of small proteins (~5–20 kDa) important in cell signaling. Cytokine_sentence_1

Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokine_sentence_2

Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Cytokine_sentence_3

Their definite distinction from hormones is still part of ongoing research. Cytokine_sentence_4

Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors (despite some overlap in the terminology). Cytokine_sentence_5

Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell. Cytokine_sentence_6

They act through cell surface receptors and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Cytokine_sentence_7

Some cytokines enhance or inhibit the action of other cytokines in complex ways. Cytokine_sentence_8

They are different from hormones, which are also important cell signaling molecules. Cytokine_sentence_9

Hormones circulate in higher concentrations, and tend to be made by specific kinds of cells. Cytokine_sentence_10

Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction. Cytokine_sentence_11

The word comes from Greek: cyto, from Greek "κύτος" kytos "cavity, cell" + kines, from Greek "κίνησις" kinēsis "movement". Cytokine_sentence_12

Discovery Cytokine_section_0

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication. Cytokine_sentence_13

The activity of interferon-gamma (the sole member of the interferon type II class) was described in 1965; this was the first identified lymphocyte-derived mediator. Cytokine_sentence_14

Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom. Cytokine_sentence_15

In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines". Cytokine_sentence_16

In 1974, Stanley Cohen published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. Cytokine_sentence_17

This led to his proposal of the term cytokine. Cytokine_sentence_18

Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors. Cytokine_sentence_19

Difference from hormones Cytokine_section_1

Classic hormones circulate in nanomolar (10 M) concentrations that usually vary by less than one order of magnitude. Cytokine_sentence_20

In contrast, some cytokines (such as IL-6) circulate in picomolar (10 M) concentrations that can increase up to 1,000 times during trauma or infection. Cytokine_sentence_21

The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Cytokine_sentence_22

Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α. Cytokine_sentence_23

In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas. Cytokine_sentence_24

The current terminology refers to cytokines as immunomodulating agents. Cytokine_sentence_25

A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic rather than local. Cytokine_sentence_26

For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxis, chemokinesis and endocrine as a pyrogen. Cytokine_sentence_27

Essentially, cytokines are not limited to their immunomodulatory status as molecules. Cytokine_sentence_28

Nomenclature Cytokine_section_2

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Cytokine_sentence_29

Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete. Cytokine_sentence_30

Cytokine_unordered_list_0

  • The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally white blood cells (leukocytes). It is now used largely for designation of newer cytokine molecules and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.Cytokine_item_0_0
  • Lymphokines: produced by lymphocytesCytokine_item_0_1
  • Monokines: produced exclusively by monocytesCytokine_item_0_2
  • Interferons: involved in antiviral responsesCytokine_item_0_3
  • Colony stimulating factors: support the growth of cells in semisolid mediaCytokine_item_0_4
  • Chemokines: mediate chemoattraction (chemotaxis) between cells.Cytokine_item_0_5

Classification Cytokine_section_3

Structural Cytokine_section_4

Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types: Cytokine_sentence_31

Cytokine_unordered_list_1

  • The four-α-helix bundle family (InterPro: ): member cytokines have three-dimensional structures with a bundle of four α-helices. This family, in turn, is divided into three sub-families:Cytokine_item_1_6
    1. the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO). They can be grouped into long-chain and short-chain cytokines by topology. Some members share the common gamma chain as part of their receptor.Cytokine_item_1_7
    2. the interferon (IFN) subfamily.Cytokine_item_1_8
    3. the IL-10 subfamily.Cytokine_item_1_9
  • The IL-1 family, which primarily includes IL-1 and IL-18.Cytokine_item_1_10
  • The cysteine knot cytokines () include members of the transforming growth factor beta superfamily, including TGF-β1, TGF-β2 and TGF-β3.Cytokine_item_1_11
    • The IL-17 family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.Cytokine_item_1_12

Functional Cytokine_section_5

A classification that proves more useful in clinical and experimental practice outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1 (TNFα, IFN-γ, etc.), and those that enhance antibody responses, type 2 (TGF-β, IL-4, IL-10, IL-13, etc.). Cytokine_sentence_32

A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Cytokine_sentence_33

Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders. Cytokine_sentence_34

Several inflammatory cytokines are induced by oxidative stress. Cytokine_sentence_35

The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidative stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a). Cytokine_sentence_36

Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury. Cytokine_sentence_37

There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway. Cytokine_sentence_38

Receptors Cytokine_section_6

Main article: Cytokine receptor Cytokine_sentence_39

In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. Cytokine_sentence_40

In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful. Cytokine_sentence_41

A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Cytokine_sentence_42

Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets. Cytokine_sentence_43

Cytokine_unordered_list_2

  • Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.Cytokine_item_2_13
  • Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).Cytokine_item_2_14
  • Interferon (type 2) family, whose members are receptors for IFN β and γ.Cytokine_item_2_15
  • Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named.Cytokine_item_2_16
  • Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.Cytokine_item_2_17
  • Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.Cytokine_item_2_18

Cellular effects Cytokine_section_7

Each cytokine has a matching cell-surface receptor. Cytokine_sentence_44

Subsequent cascades of intracellular signaling then alter cell functions. Cytokine_sentence_45

This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. Cytokine_sentence_46

The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokine_sentence_47

Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. Cytokine_sentence_48

It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. Cytokine_sentence_49

This may lead to lower therapeutic doses. Cytokine_sentence_50

It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L. Cytokine_sentence_51

Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Cytokine_sentence_52

Occasionally such reactions are seen with more widespread papular eruptions. Cytokine_sentence_53

Roles in health and disease Cytokine_section_8

Cytokines are often involved in several developmental processes during embryonic development. Cytokine_sentence_54

Cytokines are crucial for fighting off infections and in other immune responses. Cytokine_sentence_55

However, they can become dysregulated and pathological in inflammation, trauma, sepsis, and hemorrhagic stroke. Cytokine_sentence_56

Adverse effects Cytokine_section_9

Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression and Alzheimer's disease to cancer. Cytokine_sentence_57

Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity. Cytokine_sentence_58

Over-secretion of cytokines can trigger a dangerous cytokine storm syndrome. Cytokine_sentence_59

Cytokine storms may have been the cause of severe adverse events during a clinical trial of TGN1412. Cytokine_sentence_60

Cytokine storms are also suspected to be the main cause of death in the 1918 "Spanish Flu" pandemic. Cytokine_sentence_61

Deaths were weighted more heavily towards people with healthy immune systems, because of their ability to produce stronger immune responses, with dramatic increases in cytokine levels. Cytokine_sentence_62

Another example of cytokine storm is seen in acute pancreatitis. Cytokine_sentence_63

Cytokines are integral and implicated in all angles of the cascade, resulting in the systemic inflammatory response syndrome and multi-organ failure associated with this intra-abdominal catastrophe. Cytokine_sentence_64

In the COVID-19 pandemic, some deaths from COVID-19 have been attributable to cytokine release storms. Cytokine_sentence_65

Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in COVID-19 infections. Cytokine_sentence_66

Medical use as drugs Cytokine_section_10

Some cytokines have been developed into protein therapeutics using recombinant DNA technology. Cytokine_sentence_67

Recombinant cytokines being used as drugs as of 2014 include: Cytokine_sentence_68

Cytokine_unordered_list_3

See also Cytokine_section_11

Credits to the contents of this page go to the authors of the corresponding Wikipedia page: en.wikipedia.org/wiki/Cytokine.